Modeling the Photochemistry of the Reference Phototoxic Drug Lomefloxacin by Steady-State and Time-Resolved Experiments, and DFT and Post-HF Calculations
✍ Scribed by Mauro Freccero; Elisa Fasani; Mariella Mella; Ilse Manet; Sandra Monti; Angelo Albini
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 635 KB
- Volume
- 14
- Category
- Article
- ISSN
- 0947-6539
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✦ Synopsis
Abstract
The irradiation in water of 1‐ethyl‐6,8‐difluoro‐7(3‐methylpiperazino)3‐quinolone‐2‐carboxylic acid (lomefloxacin), a bactericidal agent whose use is limited by its serious phototoxicity (and photomutagenicity in the mouse), leads to formation of the aryl cation in position eight that inserts into the 1‐ethyl chain. Trapping of the cation was examined and it was found that chloride and bromide straightforwardly add in position eight, but with iodide and with pyrrole the 1‐(2‐iodoethyl) and the 1‐[2‐(2‐pyrrolyl)ethyl] derivatives are formed. Flash photolysis reveals the triplet of lomefloxacin, a short‐lived species (λ~max~=370 nm, τ=40 ns) that generates the triplet cation (λ~max~=480 nm, τ≈120 ns). The last intermediate is quenched both by halides and by pyrrole. DFT and post‐HF methods have shown that the triplet is the lowest state of the cation (Δ__G__~ST~=13.3 kcal mol^−1^) and intersystem crossing (ISC) to the singlet has no role because a less endothermic process occurs, that is, intramolecular hydrogen abstraction from the N‐ethyl chain (9.2 kcal mol^−1^) that finally leads to cyclization. The halides form weak complexes with the triplet cation (k~q~ from 4.9×10^8^ for Cl^−^ to 7.0×10^9^ m^−1^ s^−1^ for I^−^). With Cl^−^ and Br^−^ ISC occurs in the complex along with C~8~X bond formation. However, this latter process is slow with bulky iodide and with neutral pyrrole, and in these cases moderately endothermic electron transfer (ca. 7 kcal mol^−1^) yielding the 8‐quinolinyl radical occurs. Hydrogen exchange leads to a new radical on the 1‐ethyl chain and to the observed products. These findings suggest that the mutagenic activity of the DNA‐intercalated drug involves attack of the photogenerated cation to the heterocyclic bases.